A polysaccharide vaccine* against invasive (bacteremic) disease
caused by
Haemophilus influenzae type b recently has been licensed in the
United
States. The purposes of this statement are to summarize available
information
about this vaccine and to offer guidelines for its use in the
prevention of
invasive H. influenzae type b disease.

HAEMOPHILUS INFLUENZAE DISEASE

H. influenzae is a leading cause of serious systemic bacterial
disease in
the United States. It is the most common cause of bacterial
meningitis,
accounting for an estimated 12,000 cases annually, primarily among
children
under 5 years of age. The mortality rate is 5%, and neurologic
sequelae are
observed in as many as 25%-35% of survivors. Virtually all cases of
H.
influenzae meningitis among children are caused by strains of type
b (Hib),
although this capsular type represents only one of the six types
known for
this species. In addition to bacterial meningitis, Hib is
responsible for
other invasive diseases, including epiglottitis, sepsis,
cellulitis, septic
arthritis, osteomyelitis, pericarditis, and pneumonia. Nontypeable
(noncap-
sulated) strains of H. influenzae commonly colonize the human
respiratory
tract and are a major cause of otitis media and respiratory mucosal
infection
but rarely result in bacteremic disease. Hib strains account for
only 5%-10%
of H. influenzae causing otitis media.

Several population-based studies of invasive Hib disease
conducted within
the last 10 years have provided estimates of the incidence of
disease among
children under 5 years of age, the major age group at risk. These
studies
have demonstrated attack rates of meningitis ranging from 51 cases
per
100,000 children to 77/100,000 per year and attack rates of other
invasive
Hib disease varying from 24/100,000 to 75/100,000 per year (1).
Thus, in the
United States, approximately one of every 1,000 children under 5
years of age
develops systemic Hib disease each year, and a child's cumulative
risk of
developing systemic Hib disease at some time during the first 5
years of life
is about one in 200. Attack rates peak between 6 months and 1 year
of age and
decline thereafter. Approximately 35%-40% of Hib disease occurs
among
children 18 months of age or older, and 25% occurs above 24 months
of age.

Incidence rates of Hib disease are increased in certain
high-risk groups,
such as Native Americans (both American Indians and Eskimos),
blacks, indi-
viduals of lower socioeconomic status, and patients with asplenia,
sickle
cell disease, Hodgkin's disease, and antibody deficiency syndromes.
Recent
studies also have suggested that the risk of acquiring primary Hib
disease
for children under 5 years of age appears to be greater for those
who attend
day-care facilities than for those who do not (2,3).

The potential for person-to-person transmission of systemic Hib
disease
among susceptible individuals has been recognized in the past
decade. Studies
of secondary spread of Hib disease in household contacts of index
patients
have shown a substantially increased risk of disease among exposed
household
contacts under 4 years of age (4). In addition, numerous clusters
of cases in
day-care facilities have been reported, and recent studies suggest
that
secondary attack rates in day-care classroom contacts of a primary
case also
may be increased (5,6).

HAEMOPHILUS b POLYSACCHARIDE VACCINE

The Hib vaccine is composed of the purified, capsular
polysaccharide of
H. influenzae type b ({-->3} ribose-B1 -->1 ribitol-1
phosphate-5-->).
Antibodies to this antigen correlate with protection against
invasive
disease. The Hib vaccine induces an antibody response that is
directly
related to the age of the recipient; infants respond infrequently
and with
less antibody than do older children or adults (7). Improved
responses are
observed by 18 months of age, although children 18-23 months of age
do not
respond as well as those 2 years of age or older. The frequency and
magnitude
of antibody responses reach adult levels at about 6 years of age
(8,9).
Levels of antibodies to the capsular polysaccharide also decline
more rapidly
in immunized infants and young children than in adults.

In a manner similar to other polysaccharide antigens,
revaccination with
Hib vaccine results in a level of antibody comparable to that for a
child of
the same age receiving a first immunization (10). Such
polysaccharide
antigens have been termed "T-cell independent" because of their
failure to
induce the T-cell memory response characteristic of protein
antigens.

Limited data are available on the response to Hib vaccine in
high-risk
groups with underlying disease. By analogy to pneumococcal vaccine,
patients
with sickle cell disease or asplenia are likely to exhibit an
immune response
to the Hib vaccine. Patients with malignancies associated with
immunosup-
pression appear to respond less well. Additional data on the immune
response
to Hib vaccine in these groups are needed.

A precise protective level of antibody has not been
established. However,
based on evidence from passive protection in the infant rat model
and from
experience with agammaglobulinemic children, an antibody
concentration of
0.15 ug/ml correlates with protection (7,8,11). In the Finnish
field trial,
levels of capsular antibody greater than 1 ug/ml in 3-week
postimmunization
sera correlated with clinical protection for a minimum of 1 1/2
years
(9,12,13). Approximately 75% of children 18-23 months of age tested
achieved
a level greater than 1 ug/ml, as did 90% of 24-35 month old
children (9).
Measurement of Hib antibody levels is not routinely available,
however, and
determination of antibody levels following vaccination is not
indicated in
the usual clinical setting.

EFFECTIVENESS OF VACCINE

In 1974, a randomized, controlled trial of clinical efficacy
was
conducted in Finland among children 3-71 months of age (9).
Approximately
98,000 children, half of whom received the Hib vaccine, were
enrolled in the
field trial and followed for a 4-year period for occurrence of Hib
disease.
Among children 18-71 months of age, 90% protective efficacy (95%
confidence
limits, 55%-98%) in prevention of all forms of invasive Hib disease
was
demonstrated for the 4-year follow-up period. Although no disease
occurred
among over 4,000 children 18-23 months of age immunized with Hib
vaccine and
followed for 4 years, only two cases occurred in the control
vaccine recip-
ients in this age group. As a result, vaccine efficacy in the
subgroup of
children immunized at 18-23 months of age could not be evaluated
statis-
tically. The vaccine was not efficacious in children under 18
months of age.

REVACCINATION

Limited data regarding the potential need for revaccination
are
available at present. Current data show that children who have
received the
Hib vaccine 2-42 months previously have an immune response to the
vaccine
similar to that in previously unvaccinated children of the same
age. No
immunologic tolerance or impairment of immune response to a
subsequent dose
of vaccine occurs (10). As with other polysaccharide vaccines, the
shorter
persistence of serum antibodies in young children given Hib
vaccine, compared
with adults, suggests that a second dose of vaccine may be needed
to maintain
immunity throughout the period of risk, particularly for children
in the
youngest age group considered for vaccination (those 18-23 months
of age). A
second injection following the initial dose is likely to increase
the
protective benefit of vaccination for this high-risk group, because
antibody
titers 18 months after vaccination, although detectable in most
vaccine
recipients, are no longer significantly different from those in
unvaccinated
children of the same age.

RECOMMENDATIONS FOR VACCINE USE

Recently published data regarding vaccine efficacy and the risk
of Hib
disease among young children strongly support the use of Hib
vaccine in the
United States in high-risk persons for whom efficacy has been
established.
Specific recommendations are as follows:

Immunization of all children at 24 months of age is
recommended. The
precise duration of immunity conferred by a single dose of
Hib vaccine
at 24 months of age is not known, although, based on
available data,
protection is expected to last 1 1/2-3 1/2 years. Until
further data
are available to determine whether an additional dose of
vaccine may
be necessary to ensure long-lasting immunity, routine
revaccination is
not recommended.

Immunization of children at 18 months of age, particularly
those in
known high-risk groups, may be considered. Although the
precise
efficacy of the vaccine among children 18-23 months of age
is not
known, this age group accounts for approximately 12% of all
invasive
Hib disease among children under 5 years of age, and Hib
vaccine has
been shown by serologic methods to be immunogenic in most
children of
this age group. However, physicians and parents should be
informed
that the vaccine is not likely to be as effective in this
age group as
in older children. These younger children may need a second
dose of
vaccine within 18 months following the initial dose to
ensure
protection. Additional data regarding the duration of the
antibody
response are needed to define the timing of a second dose
more
precisely.

Children who attend day-care facilities are at
particular risk of
acquiring systemic Hib disease. Initial vaccination at 18
months of
age for this high-risk group should be considered.

Children with chronic conditions known to be associated
with
increased risk for Hib disease should receive the vaccine,
although
only limited data on immunogenicity and clinical efficacy in
this
group are available. These conditions include anatomic or
functional
asplenia, such as sickle cell disease or splenectomy (14),
and malig-
nancies associated with immunosuppression (15).

Immunization of individuals over 24 months of age who have
not yet
received Hib vaccine should be based on risk of disease. The
risk of
invasive Hib disease decreases with increasing age over the
age of 2
years. Because the vaccine is safe and effective, however,
physicians
may wish to immunize previously unvaccinated healthy
children between
2 years and 5 years of age to prevent the Hib disease that
does occur
in this age group. The potential benefit of this strategy in
terms of
cases prevented declines with increasing age of the child at
the time
of vaccination. Therefore, children 2-3 years of age who
attend day-
care facilities should be given a higher priority than
day-care
attendees who are 4-5 years old.

Insufficient data are available on which to base a
recommendation
concerning use of the vaccine in older children and adults
with the
chronic conditions associated with an increased risk of Hib
disease.

Vaccine is not recommended for children under 18 months of
age.

Simultaneous administration of Hib and DTP vaccines at
separate sites
can be performed, because no impairment of the immune
response to the
individual antigens occurs under these circumstances.

SIDE EFFECTS AND ADVERSE REACTIONS

Polysaccharide vaccines are among the safest of all vaccine
products. To
date, over 60,000 doses of the Hib polysaccharide vaccine have been
admin-
istered to infants and children, and several hundred doses have
been given to
adults (9,16). Only one serious systemic reaction has been reported
thus far-
-a possible anaphylactic reaction that responded promptly to
epinephrine.
High fever (38.5 C {101.3 F} or higher) has been reported in fewer
than 1% of
Hib vaccine recipients. Mild local and febrile reactions were
common,
occurring in as many as half of vaccinated individuals in the
Finnish trial.
Such reactions appeared within 24 hours and rapidly subsided.
Current
preparations appear to result in fewer such local reactions.
Simultaneous
administration with DTP does not result in reaction rates above
those
expected with separate administration (17).

PRECAUTIONS AND CONTRAINDICATIONS

The Hib vaccine is unlikely to be of substantial benefit in
preventing
the occurrence of secondary cases, because children under 2 years
old are at
highest risk of secondary disease. Because the vaccine will not
protect
against nontypeable strains of H. influenzae, recurrent upper
respiratory
diseases, including otitis media and sinusitis are not considered
indications
for vaccination.

NEW VACCINE DEVELOPMENT

New vaccines, such as the Hib polysaccharide-protein conjugate
vaccines,
are being developed and evaluated and may prove to be efficacious
for
children under 18 months of age.

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